Abstract
Embryonic development is tightly controlled. The clustered genes of the Hox family of homeobox proteins play an important part in regulating this development and also proliferation. They specify embryonic structures along the body axis, and are associated with normal and malignant cell growth. The cell-cycle regulator geminin controls replication by binding to the licensing factor Cdt1, and is involved in neural differentiation. Here, we show that murine geminin associates transiently with members of the Hox-repressing polycomb complex, with the chromatin of Hox regulatory DNA elements and with Hox proteins. Gain- and loss-of-function experiments in the chick neural tube demonstrate that geminin modulates the anterior boundary of Hoxb9 transcription, which suggests a polycomb-like activity for geminin. The interaction between geminin and Hox proteins prevents Hox proteins from binding to DNA, inhibits Hox-dependent transcriptional activation of reporter and endogenous downstream target genes, and displaces Cdt1 from its complex with geminin. By establishing competitive regulation, geminin functions as a coordinator of developmental and proliferative control.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding, Competitive
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Cycle*
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Cell Line, Tumor
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Chick Embryo
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DNA / antagonists & inhibitors
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Electrophoretic Mobility Shift Assay
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism
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Geminin
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Gene Expression Regulation, Developmental*
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Homeodomain Proteins / antagonists & inhibitors*
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Mice
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Molecular Sequence Data
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Nuclear Proteins
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Oncogene Proteins / antagonists & inhibitors
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Polycomb-Group Proteins
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Protein Binding
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism*
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Response Elements / genetics
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Transcription, Genetic / genetics
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Geminin
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Gmnn protein, mouse
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HOXB9 protein, human
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Homeodomain Proteins
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Hoxb9 protein, mouse
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Nuclear Proteins
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Oncogene Proteins
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Polycomb-Group Proteins
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Repressor Proteins
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Tlx1 protein, mouse
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Fibroblast Growth Factor 2
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DNA